Novel Skin Lightening Agents, Compositions and Methods

ABSTRACT

Compounds of formula I, process for making same, and cosmetic compositions and methods of skin lightening using compounds of formula I as skin lightening agents: 
     
       
         
         
             
             
         
       
     
     Where each A 1  and/or A 2  independently is ═H or COR, CO 2 R, CONHR, the latter three having the following formula A: 
     
       
         
         
             
             
         
       
     
     where R═C 1 -C 18  saturated or unsaturated, linear or branched, hydrocarbon; and
 
each Y 1  and/or Y 2  independently is H; C 1 -C 18  saturated or unsaturated hydrocarbon; or OZ, where Z=H or COR 1 , CO 2 R 1 , CONHR 1  of formula B:
 
     
       
         
         
             
             
         
       
     
     and where R 1 ═C 1 -C 18  saturated or unsaturated, linear or branched, hydrocarbon;
 
X is Carbon, Nitrogen, Sulfur, or Oxygen; and N is in integer between 0 and 2.

This application claims priority under 35 U.S.C. 119 from U.S.provisional application Ser. No. 60/432,857, filed Dec. 12, 2002, andincorporated by reference herein in its entirety.

FIELD OF THE INVENTION

The invention relates to cosmetic methods of using 4-substitutedresorcinol derivative compounds and cosmetic compositions includingsame, and more specifically, 1,3-dithiane resorcinol derivatives, asskin lightening agents.

BACKGROUND OF THE INVENTION

Many people are concerned with the degree of pigmentation of their skin.For example, people with age spots or freckles may wish such pigmentedspots to be less pronounced. Others may wish to reduce the skindarkening caused by exposure to sunlight or to lighten their naturalskin color. To meet this need, many attempts have been made to developproducts that reduce the pigment production in the melanocytes. However,the substances identified thus far tend to have either low efficacy orundesirable side effects, such as, for example, toxicity or skinirritation. Therefore, there is a continuing need for new skinlightening agents, with improved overall effectiveness.

Resorcinol derivatives have cosmetic skin and hair benefits. Certainresorcinol derivatives, particularly 4-substituted resorcinolderivatives, are useful in cosmetic compositions for skin lighteningbenefits. Resorcinol derivatives are described in many publications,including Hu et al., U.S. Pat. No. 6,132,740; Collington et al., PCTPatent Application WO 00/56702; Bradley et al., European PatentApplication EP 1 134 207; Shinomiya et al., U.S. Pat. No. 5,880,314;LaGrange et al., U.S. Pat. No. 5,468,472; Hiroaki et al., JapanesePatent Application JP11-255638 A2; Torihara et al., U.S. Pat. No.4,959,393; and Japanese published patent applications JP 2001-010925 andJP2000-327557. Resorcinol derivatives are known compounds and can bereadily obtained by various means, including by a method wherein asaturated carboxylic acid and resorcinol are condensed in the presenceof zinc chloride and the resultant condensate is reduced with zincamalgam/hydrochloric acid (Lille, et al., Tr. Nauch-Issled. Inst.Slantsev 1969, No. 18:127-134), or by a method wherein resorcinol and acorresponding alkyl alcohol are reacted in the presence of an aluminacatalyst at a high temperature of from 200 to 400° C. (British PatentNo. 1,581,428). Some of these compounds can be irritating to the skin.

Applicants have now discovered novel 1,3-dithiane resorcinol compounds,which possess skin lightening benefits. The general chemical formulasand structures of these compounds are discussed in more detail hereinbelow. The 1,3-dithiane resorcinols have been found to be effective andpossibly less irritating to the skin, and are novel compounds, that havenot been used for lightening skin.

In another aspect, the present invention relates to an inventive processfor making the novel compounds of the present invention.

SUMMARY OF THE INVENTION

Compounds of the general formula I, and compositions including same,deliver skin lightening benefits. In addition to skin lighteningbenefits, an additional benefit is substantially reduced irritation. Thepresent invention provides a cosmetic composition and method of skinlightening using in addition to a cosmetically acceptable vehicle, about0.000001 to about 50% of a compound of general formula I,

Where:

each A₁ and/or A₂ independently is ═H or COR (acyl group), CO₂R, CONHRhaving the following formula A:

where R═C₁-C₁₈ saturated or unsaturated, linear or branched,hydrocarbon;each Y₁ and/or Y₂ independently is H; C₁-C₁₈ saturated or unsaturatedhydrocarbon; or OZ, where Z=H or COR¹, CO₂R¹, CONHR¹ of formula B:

and where R¹═C₁-C₁₈ saturated or unsaturated, linear or branched,hydrocarbon;X is Carbon, Nitrogen, Sulfur, or Oxygen; preferably, Carbon; andN is in integer between 0 and 2.

When N=0 (zero), X is disregarded, to that the dithiane structure is a5-member ring, and the compound has the general formula II:

In a preferred embodiment, each or both A₁ and/or A₂ represents H andeach Y₁ and/or Y₂ represents H. In a more preferred embodiment, N iszero; both A₁ and A₂ represent H, and both Y₁ and Y₂ represent H, sothat the compound is of formula III as follows:

In another aspect, the present invention relates to an inventive processfor making the novel compounds of the present invention. The compoundsof formula III, IV and V are prepared by reacting 2,4-dihydroxybenzaldehyde with 1,2-Dimercaptoethane, 1,3-Dimercaptopropane or1,4-dimercaptobutane, respectively, in the presence of an acid catalystsuch as methane sulfonic acid, p-toluene sulfonic acid, sulfuric acid,hydrochloric acid, acidic resins and mixtures thereof. Optionally, thehydroxy groups may be further substituted by methods known in the art.For example, the one or both hydroxy groups may be esterified with anyor a combination of the following acids: ferulic acid, vanillic acid,sebacic acid, azaleic acid, benzoic acid, caffeic acid, coumaric acid,salicylic acid, cysteine, cystine, lactic acid, and glycolic acid.

Further skin benefit agents may be included in the compositions usefulfor the inventive method. Organic and inorganic sunscreens may also beincluded.

The inventive compositions and methods have effective skin lighteningproperties, may be less irritating to the skin, and are cost-effectiveto prepare commercially.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term “cosmetic composition” is intended to describecompositions for topical application to human skin.

The term “skin” as used herein includes the skin on the face, neck,chest, back, arms, axilla, hands, legs, and scalp.

Except in the examples, or where otherwise explicitly indicated, allnumbers in this description indicating amounts of material or conditionsof reaction, physical properties of materials and/or use are to beunderstood as modified by the word “about”. All amounts are by weight ofthe composition, unless otherwise specified.

It should be noted that in specifying any range of concentration, anyparticular upper concentration can be associated with any particularlower concentration.

For the avoidance of doubt the word “comprising” is intended to meanincluding but not necessarily consisting of or composed of. In otherwords the listed steps or options need not be exhaustive.

Skin Lightening Agents

The invention is concerned with compounds of general formula I, shownbelow, compositions including same, process for making same, and usethereof as skin lightening agents. A particular advantage of theinventive compounds, compositions and methods is that compounds ofgeneral formula I can be less irritating to the skin than other, known,skin lightening compounds. The present invention provides a cosmeticcomposition and method of skin lightening using in addition to acosmetically acceptable vehicle, about 0.000001 to about 50% of acompound of formula I,

Where:

each A₁ and/or A₂ independently is ═H or COR, CO₂R, CONHR, the latterthree having the following formula A:

where R═C₁-C₁₈ saturated or unsaturated, linear or branched,hydrocarbon; andeach Y₁ and/or Y₂ independently is H; C₁-C₁₈ saturated or unsaturatedhydrocarbon; or OZ, where Z=H or COR¹, CO₂R¹, CONHR¹ of formula B:

and where R¹═C₁-C₁₈ saturated or unsaturated, linear or branched,hydrocarbon;X is Carbon, Nitrogen, Sulfur, or Oxygen; preferably, Carbon; andN is in integer between 0 and 2.

When N=0, X is disregarded, to that the dithiane structure is a 5-memberring, and the compound has the general formula II:

In a preferred embodiment, each or both A₁ and/or A₂ represents H andeach Y₁ and/or Y₂ represents H. In a more preferred embodiment, both A₁and A₂ represent H, and both Y₁ and Y₂ represent H, so that the compoundis of formula II as follows:

The compound of general formula II, optionally, the hydroxy groups (thehydrogen on one or both of the OH-groups) may be further substituted bymethods known in the art. For example, the one or both hydroxy groupsmay be esterified with any or a combination of the following acids:ferulic acid, vanillic acid, sebacic acid, azaleic acid, benzoic acid,caffeic acid, coumaric acid, salicylic acid, cysteine, cystine, lacticacid, and glycolic acid.

Synthetic Process Thioacetalyzation of 2,4-Dihydroxybenzaldehyde

Alkyldithiol (1.2 eq) is added to a solution of2,4-dihydroxybenzaldehyde (1.0 eq) and p-toluenesulfonic acidmonohydrate (0.1 eq) in tetrahydrofuran (0.4-0.5 M solution) at roomtemperature under a nitrogen atmosphere. Magnesium sulfate (1.0 weighteq) is added and the reaction monitored by TLC until completeconsumption of 2,4-dihydroxybenzaldehyde. The mixture is partitionedbetween ethyl acetate:saturated sodium bicarbonate, the organic layerwashed with saturated sodium chloride and the solvent removed underreduced pressure. The crude material is purified by flash chromatographyto afford pure product.

Synthesis of 4-[2′-(1′,3′-dithiacyclohexy)]-1,3-dihydroxybenzene

1,3-propanedithiol (872 uL; 8.69 mmol) was added to a solution of2,4-dihydroxybenzaldehyde (1.0 g; 7.24 mmol) and p-toluenesulfonic acidmonohydrate (140 mg; 0.72 mmol) in tetrahydrofuran (15 ml) at roomtemperature (R.T. of about 2° C. to about 25 C) under a nitrogenatmosphere. After 10 minutes, magnesium sulfate (1.0 g) was added andthe mixture stirred for 2 hours, at which point TLC (1:1 ethylacetate:hexanes) showed the clean formation of product (R_(f)=0.37) andno starting aldehyde (R_(f)=0.52). The mixture was poured into ethylacetate:saturated sodium bicarbonate (25 ml:25 ml), the organic layerwashed with saturated sodium chloride (2×25 ml) and the solvent removedunder reduced pressure to give a white solid. The crude product waswashed with toluene (3×30 ml) and purified by flash chromatography(silica gel; 1:1 ethyl acetate:hexanes) to give pure product as a whitesolid (1.35 g; 95% yield).

Synthesis of 4-[2′-(1′,3′-dithiacyclopenty)]-1,3-dihydroxybenzene

1,2-ethanedithiol (818 uL; 9.72 mmol) was added to a solution of2,4-dihydroxybenzaldehyde (1.0 g; 7.24 mmol) and p-toluenesulfonic acidmonohydrate (140 mg; 0.72 mmol) in tetrahydrofuran (15 ml) at roomtemperature under a nitrogen atmosphere. After 20 minutes, magnesiumsulfate (1.0 g) was added and the mixture stirred for 4 hours, at whichpoint TLC (1:1 ethyl acetate:hexanes) showed the clean formation ofproduct (R_(f)=0.42) and no starting aldehyde (R_(f)=0.51). The mixturewas poured into ethyl acetate:saturated sodium bicarbonate (25 ml:25ml), the organic layer washed with saturated sodium chloride (2×25 ml)and the solvent removed under reduced pressure to give a yellow oil. Thecrude product was purified by flash chromatography (silica gel; 1:1ethyl acetate:hexanes) to afford pure product as a faint pale yellow oil(1.40 g; 90%).

Synthesis of 4-[2′-(1′,3′-dithiacyclohepty)]-1,3-dihydroxybenzene

1,4-butanedithiol (1.02 mL; 8.69 mmol) was added to a solution of2,4-dihydroxybenzaldehyde (1 g; 7.24 mmol) and p-toluenesulfonic acidmonohydrate (140 mg; 0.72 mmol) in tetrahydrofuran (15 ml) at roomtemperature under a nitrogen atmosphere. After 10 minutes, magnesiumsulfate (1 g) was added and the mixture stirred for 2 hours, at whichpoint TLC (1:1 ethyl acetate:hexanes) showed the clean formation ofproduct and no starting aldehyde. The mixture was poured into ethylacetate:saturated sodium bicarbonate (25 ml:25 ml), the organic layerwashed with saturated sodium chloride (2×25 ml) and the solvent removedunder reduced pressure. The crude material was purified by flashchromatography (silica gel; 1:1 ethyl acetate:hexanes) to give pureproduct (1.57 g, 90%).

Compositions

The compounds of general formula I may be formulated in a cosmeticcomposition. The inventive compositions and methods have effective skinlightening properties, may be less irritating to the skin than otherskin lightening actives, and are relatively easy to manufacture andcost-effective.

The compositions generally contain about 0.000001 to about 50% ofcompounds of general formula I and/or II, as described hereinabove.Compounds of formula III are preferred. The amount of the inventivecompound is preferably in the range of about 0.00001% to about 10%, morepreferably about 0.001 to about 7%, most preferably from 0.01 to about5%, of the total amount of a cosmetic composition.

Optional Skin Benefit Agents

Preferred cosmetic compositions are those suitable for the applicationto human skin according to the method of the present invention, whichoptionally, but preferably, include a skin benefit agent in addition toa compound of general formula I.

Suitable additional skin benefit agents include anti-aging,wrinkle-reducing, skin whitening, anti-acne, and sebum reduction agents.Examples of these include alpha-hydroxy acids, beta-hydroxy acids,polyhydroxy acids, hydroquinone, t-butyl hydroquinone, Vitamic Cderivatives, dioic acids (e.g., malonic acid, sebacic acid), retinoids,and resorcinol derivatives other than compound of formula I of thepresent invention.

Cosmetically Acceptable Carrier

The cosmetically acceptable vehicle may act as a dilutant, dispersant orcarrier for the skin benefit ingredients in the composition, so as tofacilitate their distribution when the composition is applied to theskin.

The vehicle may be aqueous, anhydrous or an emulsion. Preferably, thecompositions are aqueous or an emulsion, especially water-in-oil oroil-in-water emulsion, preferably oil in water emulsion. Water whenpresent will be in amounts which may range from 5 to 99%, preferablyfrom 20 to 70%, optimally between 40 and 70% by weight.

Besides water, relatively volatile solvents may also serve as carrierswithin compositions of the present invention. Most preferred aremonohydric C₁-C₃ alkanols. These include ethyl alcohol, methyl alcoholand isopropyl alcohol. The amount of monohydric alkanol may range from 1to 70%, preferably from 10 to 50%, optimally between 15 to 40% byweight.

Emollient materials may also serve as cosmetically acceptable carriers.These may be in the form of silicone oils and synthetic esters. Amountsof the emollients may range anywhere from 0.1 to 50%, preferably between1 and 20% by weight.

Silicone oils may be divided into the volatile and non-volatile variety.The term “volatile” as used herein refers to those materials which havea measurable vapor pressure at ambient temperature. Volatile siliconeoils are preferably chosen from cyclic or linear polydimethylsiloxanescontaining from 3 to 9, preferably from 4 to 5, silicon atoms. Linearvolatile silicone materials generally have viscosities less than about 5centistokes at 25° C. while cyclic materials typically have viscositiesof less than about 10 centistokes. Nonvolatile silicone oils useful asan emollient material include polyalkyl siloxanes, polyalkylarylsiloxanes and polyether siloxane copolymers. The essentiallynon-volatile polyalkyl siloxanes useful herein include, for example,polydimethyl siloxanes with viscosities of from about 5 to about 25million centistokes at 25° C. Among the preferred non-volatileemollients useful in the present compositions are the polydimethylsiloxanes having viscosities from about 10 to about 400 centistokes at25° C.

Among the ester emollients are:

-   -   (1) Alkenyl or alkyl esters of fatty acids having 10 to 20        carbon atoms. Examples thereof include isoarachidyl        neopentanoate, isononyl isonanonoate, oleyl myristate, oleyl        stearate, and oleyl oleate.    -   (2) Ether-esters such as fatty acid esters of ethoxylated fatty        alcohols.    -   (3) Polyhydric alcohol esters. Ethylene glycol mono and di-fatty        acid esters, diethylene glycol mono- and di-fatty acid esters,        polyethylene glycol (200-6000) mono- and di-fatty acid esters,        propylene glycol mono- and di-fatty acid esters, polypropylene        glycol 2000 monooleate, polypropylene glycol 2000 monostearate,        ethoxylated propylene glycol monostearate, glyceryl mono- and        di-fatty acid esters, polyglycerol poly-fatty esters,        ethoxylated glyceryl mono-stearate, 1,3-butylene glycol        monostearate, 1,3-butylene glycol distearate, polyoxyethylene        polyol fatty acid ester, sorbitan fatty acid esters, and        polyoxyethylene sorbitan fatty acid esters are satisfactory        polyhydric alcohol esters.    -   (4) Wax esters such as beeswax, spermaceti, myristyl myristate,        stearyl stearate and arachidyl behenate.    -   (5) Sterol esters, of which cholesterol fatty acid esters are        examples.

Fatty acids having from 10 to 30 carbon atoms may also be included ascosmetically acceptable carriers for compositions of this invention.Illustrative of this category are pelargonic, lauric, myristic,palmitic, stearic, isostearic, hydroxystearic, oleic, linoleic,ricinoleic, arachidic, behenic and erucic acids.

Humectants of the polyhydric alcohol-type may also be employed ascosmetically acceptable carriers in compositions of this invention. Thehumectant aids in increasing the effectiveness of the emollient, reducesscaling, stimulates removal of built-up scale and improves skin feel.Typical polyhydric alcohols include glycerol, polyalkylene glycols andmore preferably alkylene polyols and their derivatives, includingpropylene glycol, dipropylene glycol, polypropylene glycol, polyethyleneglycol and derivatives thereof, sorbitol, hydroxypropyl sorbitol,hexylene glycol, 1,3-butylene glycol, 1,2,6-hexanetriol, ethoxylatedglycerol, propoxylated glycerol and mixtures thereof. For best resultsthe humectant is preferably propylene glycol or sodium hyaluronate. Theamount of humectant may range anywhere from 0.5 to 30%, preferablybetween 1 and 15% by weight of the composition.

Thickeners may also be utilized as part of the cosmetically acceptablecarrier of compositions according to the present invention. Typicalthickeners include crosslinked acrylates (e.g. Carbopol 982),hydrophobically-modified acrylates (e.g. Carbopol 1382), cellulosicderivatives and natural gums. Among useful cellulosic derivatives aresodium carboxymethylcellulose, hydroxypropyl methylcellulose,hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose andhydroxymethyl cellulose. Natural gums suitable for the present inventioninclude guar, xanthan, sclerotium, carrageenan, pectin and combinationsof these gums. Amounts of the thickener may range from 0.0001 to 5%,usually from 0.001 to 1%, optimally from 0.01 to 0.5% by weight.

Collectively the water, solvents, silicones, esters, fatty acids,humectants and/or thickeners will constitute the cosmetically acceptablecarrier in amounts from 1 to 99.9%, preferably from 80 to 99% by weight.

An oil or oily material may be present, together with an emulsifier toprovide either a water-in-oil emulsion or an oil-in-water emulsion,depending largely on the average hydrophilic-lipophilic balance (HLB) ofthe emulsifier employed.

Surfactants may also be present in cosmetic compositions of the presentinvention. Total concentration of the surfactant will range from 0.1 to40%, preferably from 1 to 20%, optimally from 1 to 5% by weight of thecomposition. The surfactant may be selected from the group consisting ofanionic, nonionic, cationic and amphoteric actives. Particularlypreferred nonionic surfactants are those with a C₁₀-C₂₀ fatty alcohol oracid hydrophobe condensed with from 2 to 100 moles of ethylene oxide orpropylene oxide per mole of hydrophobe; C₂-C₁₀ alkyl phenols condensedwith from 2 to 20 moles of alkylene oxide; mono- and di-fatty acidesters of ethylene glycol; fatty acid monoglyceride; sorbitan, mono- anddi-C₈-C₂₀ fatty acids; block copolymers (ethylene oxide/propyleneoxide); and polyoxyethylene sorbitan as well as combinations thereof.Alkyl polyglycosides and saccharide fatty amides (e.g. methylgluconamides) are also suitable nonionic surfactants.

Preferred anionic surfactants include soap, alkyl ether sulfate andsulfonates, alkyl sulfates and sulfonates, alkylbenzene sulfonates,alkyl and dialkyl sulfosuccinates, C₈-C₂₀ acyl isethionates, acylglutamates, C₈-C₂₀ alkyl ether phosphates and combinations thereof.

Optional Components

In the cosmetic compositions of the invention, there may be addedvarious other thickeners, calamine; pigments; antioxidants; andchelating agents; as well as sunscreens, including organic and/orinorganic sunscreens.

Other adjunct minor components may also be incorporated into thecosmetic compositions. These ingredients may include coloring agents,opacifiers, and perfumes. Amounts of these other adjunct minorcomponents may range anywhere from 0.001% up to 20% by weight of thecomposition.

Sunscreens

For use as sunscreen, metal oxides may be used alone or in mixtureand/or in combination with organic sunscreens. Examples of organicsunscreens include but are not limited those set forth in the tablebelow:

TABLE 1 Typical Organic Sunscreens CTFA Name Trade Name SupplierBenzophenone-3 UVINUL M-40 BASF Chemical Co. Benzophenone-4 UVINUL MS-40BASF Chemical Co. Benzophenone-8 SPECRA-SORB UV-24 American CyanamideDEA Methoxycinnamate BERNEL HYDRO Bernel Chemical Ethyldihydroxypropyl-PABA AMERSCREEN P Amerchol Corp. Glyceryl PABA NIPAG.M.P.A. Nipa Labs. Homosalate KEMESTER HMS Hunko Chemical Methylanthranilate SUNAROME UVA Felton Worldwide Octocrylene UVINUL N-539 BASFChemical Co. Octyl dimethyl PABA AMERSCOL Amerchol Corp. Octylmethoxycinnamate PARSOL MCX Bernel Chemical Octyl salicylate SUNAROMEWMO Felton Worldwide PABA PABA National Starch2-Phenylbenzimidazole-5-sulphonic acid EUSOLEX 232 EM Industries TEAsalicylate SUNAROME W Felton Worldwide 3-(4-methylbenzylidene)-camphorEUSOLEX 6300 EM Industries Benzophenone-1 UVINUL 400 BASF Chemical Co.Benzophenone-2 UVINUL D-50 BASF Chemical Co. Benzophenone-6 UVINUL D-49BASF Chemical Co. Benzophenone-12 UVINUL 408 BASF Chemical Co.4-Isopropyl dibenzoyl methane EUSOLEX 8020 EM Industries Butyl methoxydibenzoyl methane PARSOL 1789 Givaudan Corp. Etocrylene UVINUL N-35 BASFChemical Co.

The amount of the organic sunscreens in the cosmetic composition ispreferably in the range of about 0.1 wt % to about 10 wt %, morepreferably about 1 wt % to 5 wt %.

Preferred organic sunscreens are PARSOL MCX and Parsol 1789, due totheir effectiveness and commercial availability.

Perfumes

Perfumes are fragrance compositions that are mixtures of componentsproviding, usually, a pleasing sense of smell. Terpenes and terpenederivatives are often an important component of fragrances. Fragranceterpenes and derivatives are described in Bauer, K., et al., CommonFragrance and Flavor Materials, VCH Publishers (1990).

Terpenes and derivatives that may preferably be incorporated in theinventive cosmetic compositions are divided into three classes,including acyclic terpenoids, cyclic terpenoids, and cycloaliphaticcompounds that are structurally related to terpenoids.

Terpene derivatives within each of the three classes include alcohols,ethers, aldehydes, acetals, acids, ketones, esters, and terpenecompounds that contain heteroatoms such as nitrogen or sulfur.

Examples of terpenes and derivative that may be incorporated in thecosmetic compositions of the present invention are set forth in thetables below:

TABLE 2 Acyclic Terpenes and Derivatives HYDROCARBONS Myrcene Ocimenebeta-Farnesene ALCOHOLS Dihydromyrcenol (2,6-dimethyl-7-octen-2-ol)Geraniol (3,7-dimethyl-trans-2,6-octadien-1-ol) Nerol(3,7-dimethyl-cis-2,6-octadien-1-ol) Linalool(3,7-dimethyl-1,6-octadien-3-ol) Myrcenol(2-methyl-6-methylene-7-octen-2-ol) Lavandulol Citronellol(3,7-dimethyl-6-octen-1-ol) Trans-trans-Farnesol(3,7,11-trimethyl-2,6,10-dodecatrien-1-ol) Trans-Nerolidol(3,7,11-trimethyl-1,6,10-dodecatrien-3-ol) ALDEHYDES AND ACETALS Citral(3,7-dimethyl-2,6-octadien-1-al) Citral diethyl acetal(3,7-dimethyl-2,6-octadien-1-al diethyl acetal) Citronellal(3,7-dimethyl-6-octen-1-al) Citronellyloxyacetaldehyde2,6,10-Trimethyl-9-undecenal KETONES Tagetone Solanone Geranylacetone(6,10-dimethyl-5,9-undecadien-2-one) ACIDS AND ESTERS Cis-Geranic acidCitronellic acid Geranyl Esters, including Geranyl formate, Geranylacetate, Geranyl propionate, Geranyl isobutyrate, Geranyl isovalerateNeryl Esters, including Neryl acetate Linalyl Esters, including Lynalylformate, Linalyl acetate, Linalyl propionate, Linalyl butyrate, Linalylisobutyrate, Lavandulyl Esters, including Lavendulyl acetate CitronellylEsters, including Citronellyl formate, Citronellyl acetate, Citronellylpropionate, Citronellyl isobutyrate, Citronellyl isovalerate,Citronellyl tiglate NITROGEN CONTAINING UNSATURATED TERPENE DERIVATIVESCis-Geranic acid nitrile Citronellic acid nitrile

TABLE 3 Cyclic Terpenes and Derivatives HYDROCARBONS Limonene(1,8-p-menthadiene) Alpha-Terpinene Gamma-Terpinene (1,4-p-menthadiene)Terpinolene Alpha-Phellandrene (1,5-p-menthadiene) Beta-PhellandreneAlpha-Pinene (2-pinene) Beta-Pinene (2(10)-pinene) Camphene 3-CareneCaryophyllene (+)-Valencene Thujopsene Alpha-Cedrene Beta-CedreneLongifolene ALCOHOLS AND ETHERS (+)-Neoiso-isopulegol Isopulegol(8-p-menten-3-ol) Alpha-Terpineol (1-p-menten-8-ol) Beta-TerpineolGamma-Terpineol Delta-Terpineol 1-Terpinen-4-ol (1-p-menten-4-ol)ALDEHYDES AND KETONES Carvone (1,8-p-mantadien-6-one) Alpha-Ionone(C₁₃H₂₀O) Beta-Ionone (C₁₃H₂₀O) Gamma-Ionone (C₁₃H₂₀O) Irone, alpha-,beta-, gamma- (C₁₄H₂₂O) n-Methylionone, alpha-, beta-, (C₁₄H₂₂O) gamma-Isomethylionone, alpha-, beta-, (C₁₄H₂₂O) gamma- Allylionone (C₁₆H₂₄O)Pseudoionone n-Methylpseudoionone Isomethylpseudoionone Damascones1-(2,6,6-trimethylcyclohexenyl)- 2-buten-1-ones Includingbeta-Damascenone 1-(2,6,6-trimethyl-1,3- cyclohadienyl)-2-buten-1- oneNootkatone 5,6-dimethyl-8- isopropenylbicyclo[4.4.0]-1- decen-3-oneCedryl methyl ketone (C₁₇H₂₆O) ESTERS Alpha-Terpinyl acetate(1-p-menthen-8-yl acetate) Nopyl acetate(−)-2-(6,6-dimethylbicyclo[3.1.1]hept- 2-en-2-yl)ethyl acetate Khusymilacetate

TABLE 4 Cycloaliphatic Compounds Structurally Related to TerpenesALCOHOLS 5-(2,2,3-Trimethyl-3-cyclopenten- 1-yl)-3-methylpentan-2-olALDEHYDES 2,4-Dimethyl-3-cyclohexene carboxaldehyde4-(4-Methyl-3-penten-1-yl)-3- cyclohexene carboxaldehyde4-(4-Hydroxy-4-methypentyl)-3- cyclohexene carboxaldehyde KETONESCivetone Dihydrojasmone (3-methyl-2-pentyl-2- cyclopenten-1-one)Cis-Jasmone 3-methyl-2-(2-cis-penten-1-yl)- 2-cyclopenten-1-one5-Cyclohexadecen-1-one 2,3,8,8-Tetramethyl-1,2,3,4,5,6,7,8-octahydro-2-napthalenyl methyl ketone 3-methyl-2-cyclopenten-2-ol-1-oneESTERS 4,7-Methano-3a,4,5,6,7,7a-hexahydro- 5-(or 6)-indenyl acetateAllyl 3-cyclohexylpropionate Methyl dihydrojasmonate methyl(3-oxo-2-pentylcyclopentyl)acetate

Preferably, the amount of terpenes and derivatives in the cosmeticcomposition is in the range of about 0.000001% to about 10%, morepreferably about 0.00001% to about 5 wt %, most preferably about 0.0001%to about 2%.

Use of the Composition

The method according to the invention is intended primarily as using apersonal care product for topical application to human skin.

In use, a small quantity of the composition, for example from 1 to 5 ml,is applied to exposed areas of the skin, from a suitable container orapplicator and, if necessary, it is then spread over and/or rubbed intothe skin using the hand or fingers or a suitable device.

Product Form and Packaging

The cosmetic composition useful for the method of the invention can beformulated as a lotion having a viscosity of from 4,000 to 10,000 mPa·s,a fluid cream having a viscosity of from 10,000 to 20,000 mPa·s or acream having a viscosity of from 20,000 to 100,000 mPa·s, or above. Thecomposition can be packaged in a suitable container to suit itsviscosity and intended use by the consumer. For example, a lotion orfluid cream can be packaged in a bottle or a roll-ball applicator or apropellant-driven aerosol device or a container fitted with a pumpsuitable for finger operation. When the composition is a cream, it cansimply be stored in a non-deformable bottle or squeeze container, suchas a tube or a lidded jar. When the composition is a solid or semi-solidstick, it may be packaged in a suitable container for manually ormechanically pushing out or extruding the composition.

The invention accordingly also provides a closed container containing acosmetically acceptable composition as herein defined.

The following examples are by way of example, not by way of limitation,of the principles of the present invention, to illustrate the best modeof carrying out the invention.

Example 1 Procedure for Making 1,3-dithiane Resorcinol

The compound of formula III was prepared in accordance with the processdiscussed hereinbelow and used throughout the examples that follow:

In a most preferred embodiment designated by the compound of formula II,N is zero; each A₁ and A₂ represents H, both Y₁ and Y₂ represent H,because it is most cost-effective to manufacture. This most preferredembodiment, referred to herein as 1,3-dithiane resorcinol, may beprepared by reaction of 2,4-dihydroxy benzaldehyde and1,3-Dimercaptoethane (Both starting materials are available fromYick-Vic Chemicals & Pharmaceuticals (HK) Ltd/Hong Kong), denoted by thefollowing formula III and catalyzed by an acid catalyst. Suitablecatalysts include but are not limited to methane sulfonic acid,p-toluene sulfonic acid, H₂SO₄ (sulfuric acid), HCl (hydrochloric acid)and acidic resins.

A three necked flask equipped with a Dean-Stark apparatus, an additionalfunnel and a condenser is charged with 2,4-dihydroxy benzaldehyde (1equ.). To this was added toluene (500 ml) and a catalytic amount ofp-toluene sulfonic acid. The mixture was heated at 120 C. One equivalentof 1,3-dithioethane in toluene (100 ml) was added drop-wise to themixture. The mixture was stirred at reflux up to 12 hours. The solventwas removed on a rotavap and the expected product was isolated. Thestructure of the dithiane was confirmed using Mass spectroscopy, NMR andIR.

Example 2 Cosmetic Compositions within the Scope of the Invention werePrepared

A base formulation shown in Table 3, below, was made by heating phase

A ingredients to 70 to 85° C. with stirring. Phase B ingredients wereheated in a separate container to 70 to 85° C. with stirring. Then,phase A was added into phase B while both phases were kept at 70 to 85°C. The mixture was stirred for at least 15 minutes at 70 to 85° C., thencooled.

A base formulation is shown in the table below.

TABLE 5 a b Ingredients % wt. % wt. Phase Isostearyl Palmitate 6.00 6.00A C12-C15 Alkyl Octanoate 3.00 3.00 A PEG-100 Stearate 2.00 2.00 AGlyceryl Hydroxystearate 1.50 1.50 A Stearyl Alcohol 1.50 1.50 A Stearicacid 3.00 4.00 A TEA, 99% 1.20 1.20 B Dimethicone 1.00 1.00 A SorbitanMonostearate 1.00 1.00 A Magnesium Aluminum Silicate 0.60 0.60 B VitaminE acetate 0.10 0.10 A Cholesterol 0.50 0.50 A Simethicone 0.01 0.01 BXanthan gum 0.20 0.20 B Hydroxyethylcellulose 0.50 0.50 B Propylparaben0.10 0.10 B Disodium EDTA 0.05 0.05 B Butylated hydroxytolene 0.05 0.05B Compound of Formula III 0.05 2.00 B Niacinamide 1.00 1.00 B Metaloxide 2.50 5.00 B Methylparaben 0.15 0.15 B Water BAL* BAL* B Total100.00 100.00 B *BAL means Balance.

Example 3

Additional cosmetic compositions within the scope of the invention wereprepared.

TABLE 6 Wt % Phase water, DI BALANCE A disodium EDTA 0.05 A magnesiumaluminum silicate 0.6 A methyl paraben 0.15 A simethicone 0.01 Abutylene glycol 1,3 3.0 A hydroxyethylcellulose 0.5 A glycerine, USP 2.0A xanthan gum 0.2 A triethanolamine 1.2 B stearic acid 3.0 B propylparaben NF 0.1 B glyceryl hydroxystearate 1.5 B stearyl alcohol 1.5 Bisostearyl palmitate 6.0 B C12-15 alcohols octanoate 3.0 B dimethicone1.0 B cholesterol NF 0.5 B sorbitan stearate 1.0 B Micronized titaniumdioxide 5.0 C tocopheryl acetate 0.1 B PEG-100 stearate 2.0 B sodiumstearoyl lactylate 0.5 B hydroxycaprylic acid 0.1 C Compound of FormulaIII 10.0 C PARSOL MCX 2.4 C alpha-bisabolol 0.2 CThe composition of Example 3, was prepared as follows:

1. Heat Phase A to 80° C.

2. Heat Phase B to 75° C. in a separate container

3. Add B to A and mix with heat off for 30 min.

4. At 50° C. add Phase C and mix for 10 min.

Examples 4-11

A set of additional compositions useful in the methods of the presentinvention were prepared within the scope of the present invention andare listed in the table below.

TABLE 7 Examples (wt. %) 4 acid soap Ingredients Phase base 5 6 7 8 9 1011 Stearic acid A 17.9 17.9 17.9 17.9 17.9 17.9 17.9 17.9 Sodiumcetearyl A 2.2 1 1.5 2 3 2 sulfate* (emulsifier) Myrj 59* A 2 2 2 2 2 1(emulsifier) Span 60* A 2 2 2 2 2 1 (emulsifiers) Compound of B 0.050.05 2.0 2.0 3.5 3.5 5.0 10.0 Formula III Micronized Zinc B 2.50 5.005.00 2.50 2.50 5.00 2.50 5.00 Oxide KOH, 22% (form in 2.20 situ soapwith stearic acid) Octyl 2.50 2.50 2.50 2.50 methoxycinnamate Water BBAL BAL BAL BAL BAL BAL BAL BAL Glycerin B 1 1 1 1 1 1 1 1

Example 12 Mushroom Tyrosinase Assay

Mushroom tyrosinase inhibition is indicative of reduction in melaninsynthesis, thereby showing skin lightening effect. This experiment showsthe efficacy of resorcinol derivatives of the present invention.

Into each well of a 96-well plate, 150 microliters of phosphate buffer(100 mM, pH 7.0), 10 microliters of L-DOPA(L-3,4-Dihydroxyphenylalanine, 10 mM), and 20 microliters of skinlightening agent (dissolved in ethanol, which is the control) wereadded. Following an initial measurement of background absorbency at475-nm, 20 microliters of mushroom tyrosinase (Sigma T-7755; 6050units/ml) was added and incubated at room temperature.

Absorbency is read at 475-nm over the following time points: 0, 2, 4,and 6.5 minutes. The data is plotted as 475-nm absorbency vs. time(minutes) and the slope of the line is calculated (ΔAbs 475 nm/min). Inthe Table below, data is shown in terms of IC50, which is theconcentration of active needed to reduce tyrosinase synthesis by 50%versus the untreated ethanol control reaction.

TABLE 8 Mushroom Tyrosinase Assay Results IC50 (Concentration) IC50(Concentration) Compound Experiment 1 Experiment 2 4-Ethyl Resorcinol550 nano-M 400 nano-M (Positive Control) 6-member Di-Thianyl 1.7 micro-M1.0 micro-M Resorcinol 5-member Di-Thianyl 3.8 micro-M 2.5 micro-MResorcinol

The data show that the inventive compounds are substantially aseffective or slightly less effective than 4-ethyl resorcinol, bothcompounds having good skin lightening effects. An advantage of theinventive compounds is that they are relatively easy and cost-effectiveto manufacture.

It should be understood that the specific forms of the invention hereinillustrated and described are intended to be representative only.Changes, including but not limited to those suggested in thisspecification, may be made in the illustrated embodiments withoutdeparting from the clear teachings of the disclosure. Accordingly,reference should be made to the following appended claims in determiningthe full scope of the invention.

1-13. (canceled)
 14. A compound of general formula I

Wherein each A₁ and/or A₂ independently is ═H, COR, CO₂R, CONHR whereR═C₁-C₁₈ saturated or unsaturated hydrocarbon; and each Y₁ and/or Y₂independently is H, C₁-C₁₈ saturated or unsaturated hydrocarbon, or OZwhere Z=H, COR¹, CO₂R¹, CONHR¹ and wherein R¹═C₁-C₁₈ saturated orunsaturated hydrocarbon; X is Carbon, Nitrogen, Sulfur, or Oxygen; and Nis in integer between 0 and
 2. 15. The compound of claim 14, having ageneral formula II:


16. A compound of claim 14, having the formula III:


17. The compound of claim 16, wherein the hydroxy groups of saidcompound are esterified with an acid selected from the group consistingof ferulic acid, vanillic acid, sebacic acid, azaleic acid, benzoicacid, caffeic acid, coumaric acid, salicylic acid, cysteine, cystine,lactic acid, glycolic acid and mixtures thereof.
 18. A process forsynthesizing 4-[2′-(1′,3′-dithiacyclopenty)]-1,3-dihydroxybenzene,4-[2′-(1′,3′-dithiacyclohexy)]-1,3-dihydroxybenzene,4-[2′-(1′,3′-dithiacyclohepty)]-1,3-dihydroxybenzene, or mixturesthereof comprising: reacting (a) 2,4-dihydroxy benzaldehyde; with (b)1,2-Dimercaptoethane, 1,3-Dimercaptopropane, 1,4-Dimercaptobutane, ormixtures thereof, respectively; in the presence of an acid catalyst;wherein said acid catalyst is selected from the group consisting ofmethane sulfonic acid, p-toluene sulfonic acid, sulfuric acid,hydrochloric acid, acidic resins and mixtures thereof.